Programmed cell death (or apoptosis) is of central importance for the development, homeostasis, and in many diseases including cancer, acquired immunodeficiency syndrome, and neurodegenerative disorders. Under genetic control, it occurs through the activation of an intrinsic suicide program as a result of either internal or external signals. ICE/CED-3 cysteine protease family acts autonomously as effectors in dying cells. Nedd-2/Ich-1, a member of this family, was identified that can induce apoptosis in tissue culture cells. My current work suggested that ICH-1 is activated during apoptosis. The overall objective of this proposal is to characterize the functional role of ICH-1 in apoptosis,and its activation mechanism. Specific aims include: i) to examine ICH-1 activation in primary tissue culture cells, especially thymocytes and neuronal cells, when they are induced to undergo apoptosis; ii) to characterize the active form and intermediate products of ICH-1 in vivo; iii) to establish the relationship of ICH-I with other death genes; iv) to identify ICH-1 targets when it is activated.